1. Field of the Invention
The present invention relates to liquid antacid compositions and methods for their preparation. More particularly, the present invention relates to liquid antacid compositions containing a tri- or di-ester as a buffer. The compositions have a reduced final product pH providing for a more efficacious preservative system and better tasting product without compromising the acid neutralizing capacity of the antacid.
2. Description of the Related Art
Gastric antacids are agents that neutralize or remove acid from the gastric contents. Antacids are widely used in the treatment of various gastrointestinal disorders such as peptic ulcers and gastritis. Antacids are also used for the relief of acid indigestion, heartburn, dyspepsia, sour stomach, reflux esophagitis and the like. The clinical use of antacids is based on their ability to neutralize stomach acid and increase the pH of gastric secretions. Although antacids do not neutralize all gastric acid, increasing gastric pH from 1.3 to 2.3 neutralizes 90% and increasing pH to 3.3 neutralizes 99% of gastric acid. For optimal healing of peptic ulcers, most clinicians believe that gastric pH should be maintained at about 3-3.5. Accordingly, it is desirable that an antacid feature a high acid neutralization capacity and a rapid rate of gastric acid neutralization.
Antacids used today are made from a variety of inorganic salts such as calcium carbonate, sodium bicarbonate, magnesium salts and aluminum salts. Magnesium hydroxide and aluminum hydroxide are the most potent magnesium and aluminum salts and are often used in combination. In addition, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate, magnesium trisilicate, and aluminum sucrose sulfate (sucralfate) are also employed.
Antacids are available in both liquid suspensions as well as solid dosage forms. In general, liquid antacid suspensions are preferred to tablets or powders since they are more rapidly and effectively solubilized and have a greater ability to react with and neutralize gastric acid.
One of the major concerns with formulating an antacid liquid is the preservative efficacy. Liquid antacid preparations are generally susceptible to microbial contamination. The pH of any aqueous based solution is critical to controlling the microbial growth within the solution. Generally, acidic solutions (pH 3-6) are less susceptible to microbial growth than alkaline solutions (pH 8-9). Under most circumstances, the ability to restrict this microbial growth can be aided by the addition of a preservative. The degradation of the preservative in solution can in turn be affected by the pH of the finished product. In most situations, there is a perfect match between the finished product's pH and the pH range at which the preservative is most efficacious.
Some liquid antacid preparations, for example calcium carbonate, however, generally have a pH above 8.0 and no preservative systems approved in the United States function optimally at this pH. The alkyl esters of para-hydroxybenzoic acid (the parabens, e.g. butylparaben, methylparaben and propylparaben) are most widely used as preservatives because they offer the most efficacious option, but they degrade over time and this degradation process increases exponentially with an increase in pH. Consequently, in order to achieve adequate preservative levels throughout the shelf life of the product, higher levels of the preservative must be added initially. This can affect the taste of the finished product however, because preservatives such as the parabens are known to have a poor taste.
Accordingly, there is a need for a preservative system for highly alkaline liquid antacid preparations which effectively inhibits microbial contamination over the shelf life of the product without adversely affecting the taste of the finished product.
One way to inhibit degradation of the preservative would be to lower the pH of the antacid suspension. This may be done through the addition of buffers such as citric acid and tartaric acid. For example, U.S. Pat. No. 5,455,050 discloses calcium carbonate/magnesium salt antacid suspensions containing a carboxylic acid buffering agent such as tartaric acid. However, in order to lower the pH sufficiently to a level of around pH 7 where preservative degradation is minimal, large amounts of these buffers are required. The addition of such amounts of these acidic buffers can in turn adversely affect the acid neutralizing capacity of the antacid. Thus, there is a need for a method of reducing the pH of the antacid suspension to inhibit degradation of the preservative without adversely affecting the acid neutralizing capacity of the liquid antacid preparation.
Patent Application EP 0138540 describes liquid cimetidine suspensions which may contain an antacid, where the suspensions contain a buffer to maintain the pH at greater than 7 to enhance the taste of the suspension. Cimetidine has a pronounced bitter taste. The pH is preferably 7.2-7.8 and the buffer is preferably sodium citrate.